There is an undeniable link between inflammation and cancer. Virchow first noted that inflammatory cells are present within tumors and tumors arise at sites of chronic inflammation. This observation was made. 150 years ago and led to the conclusion that inflammation significantly contributes to the development of cancer. Epidemiological evidence now supports this conclusion and suggests that up to 25% of all cancers are due to chronic infection or other types of chronic inflammation. There are continued improvements to our understanding of the molecular connections between inflammation and cancer. Key mediators of inflammation-induced cancer include nuclear factor kappa B, reactive oxygen and nitrogen species, inflammatory cytokines, prostaglandins and specific microRNAs. The collective activity of these mediators is largely responsible for either a pro-tumorigenic or anti-tumorigenic inflammatory response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. As our understanding grows, inflammatory mediators will provide opportunities to develop novel diagnostic and therapeutic strategies. We have written a review that provides a general overview of the connection between inflammation, microRNAs and cancer and highlight how our improved understanding of these connections may provide novel preventive, diagnostic and therapeutic strategies to reduce the health burden of cancer. We studied the effects of reactive nitrogen species on DNA base excision repair initiated by the alkyladenine DNA glycosylase. Chronic generation of reactive nitrogen species (RNS) can cause DNA damage and may also directly modify DNA repair proteins. RNS-modified DNA is repaired predominantly by the base excision repair (BER) pathway, which includes the alkyladenine DNA glycosylase (AAG). The AAG active site contains several tyrosines and cysteines that are potential sites for modification by RNS. In vitro, we demonstrate that RNS differentially alter AAG activity depending on the site and type of modification. Nitration of tyrosine 162 impaired 1,N6-ethenoadenine (EA)-excision activity, whereas nitrosation of cysteine 167 increased EA excision. To understand the effects of RNS on BER in vivo, we examined intestinal adenomas for levels of inducible nitric oxide synthase (iNOS) and AAG. A striking correlation between AAG and iNOS expression was observed (r=0.76, P=0.00002). Interestingly, there was no correlation between changes in AAG levels and enzymatic activity. We found AAG to be nitrated in human adenomas, suggesting that this RNS modification is relevant in the human disease. Expression of key downstream components of BER, apurinic/apyrimidinic endonuclease 1 (APE1) and DNA polymerase beta (POL beta), was also examined. POL beta protein was increased in nearly all adenomas compared with adjacent non-tumor tissues, whereas APE1 expression was only increased in approximately half of the adenomas and also was relocalized to the cytoplasm in adenomas. Collectively, the results suggest that BER is dysregulated in colon adenomas. RNS-induced posttranslational modification of AAG is one mechanism of BER dysregulation, and the type of modification may define the role of AAG during carcinogenesis. We also found that macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy. Using an orthotopic model of renal cell carcinoma, we showed previously that IL-2/alpha-CD40 immunotherapy resulted in synergistic anti-tumor responses, whereas IL-2 or alpha-CD40 alone mediated partial transient anti-tumor effects. We now show that treatment of tumor-bearing mice with IL-2/alpha-CD40, but not IL-2 or alpha-CD40, induced significant nitric oxide synthase (NOS) 2 expression in tumor-associated macrophages. In control-treated mice (low NO), NOS2 inhibition reduced tumor burden. However, during immunotherapy (high NO), NOS2 inhibition or macrophage depletion reversed the ability of IL-2/alpha-CD40 treatment to reduce lung metastases but had no effect on primary tumor burden. Furthermore, IL-2/alpha-CD40 induced the IFN-gamma and NO-dependent decrease in matrix metalloproteinase (MMP) expression and activity, concomitant with increases in tissue inhibitor of metalloproteinase (TIMP) 1 and E-cadherin expression within tumors. Finally, treatment of tumor-bearing mice with the NO donor JS-K significantly reduced metastases. These data differentiate the mechanism for primary anti-tumor effects of IL-2/alpha-CD40 immunotherapy, which are independent of NO, from the NO-dependent inhibition of metastases. Furthermore, reduced MMP9 activity implicates M1-polarized macrophages within the tumor microenvironment as critical components of therapeutic response. Our data demonstrate the mechanistic basis for IL-2/alpha-CD40mediated control of metastases and suggest that the context-dependent application of NO donors may hold promise for prevention of metastatic disease.